ABSTRACT The High-Throughput Screening (HTS) Core carries out target- and phenotype-based screens of small- molecule libraries. The HTS core will support the activities of twelve CF-related screening projects, including correctors and potentiators of ?F508-CFTR, and various CF-relevant ion transport and inflammation targets. The instrumentation available for screening includes a fully automated screening platform with liquid handling and two plate readers, and two separate plate readers with stackers. Plate-readers provide fluorescence, polarization, absorbance, and luminescence readout. Functions of the Core include compound storage and handling, assay design and validation, assay execution, and data analysis. Core resources also include HPLC, LC/MS, and NMR instrumentation for compound quality control. The Core also carries out optimization of validated initial `hits' (active compounds) by screening commercially available analogs. Further `hit-to-lead' development is done on individual projects in consultation with the Synthesis Core (Core C). Having operated the HTS Core for the past 9 years, the Core established practical procedures for efficient and cost-effective compound screening, quality control, and hit-to-lead optimization.